Radiopharmaceutical Related terms: Chemistry, Technetium, Drug, Ligand, Positron, Peptide, Metal, Radioisotope Radiopharmaceuticals are drugs that contain a radionuclide and are used for imaging if the radionuclide is a photon emitter (gamma (y) or positron (B+) or for therapy if the radionuclide is a particle emitter (alpha (a), beta (B-) or ‘Auger/eonversion e-). From: Comprehensive Coordination Chemistry I, 2003 Insights from Imaging in Bioinorganic Chemistry Brett M. Paterson, Paul S. Donnelly, in Advances in Inorganic Chemistry, 2016 1 Introduction Radiopharmaceuticals use radionuclides for noninvasive molecular imaging or to deliver a therapeutic dose of ionizing radiation to tissue. Following systemic administration, radiopharmaceuticals localize within the body as a consequence of their molecular and biological properties. Radioactive molecular imaging agents are required to emit radiation that can be easily detected outside the body with minimal interference from surrounding tissue. This is achieved using gamma- or positron-emitting radioisotopes for single-photon emission computed tomography or positron emission tomography (PET), respectively. Both of these techniques can be used in combination with anatomical imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI). PET detects the two gamma photons that are produced 180° apart upon annihilation of a positron with an electron, and results in the generation of images with spatial resolution in the millimeter scale and excellent sensitivity that allows for the detection of concentrations in the range of 10°®-10-® mol/L. The majority of current PET scans image the tissue uptake of !*F-labeled 2-deoxy-d-glucose (FOG), a glucose derivative radiolabeled with '*F that serves as an excellent probe of glucose metabolism. The central role of glucose to many biological processes means that !*F-FDG is an incredibly versatile imaging agent that is used to assist in the diagnosis of a range of indications in oncology. The success of !*F-FDG has led to considerable invest ment in PET infrastructure and stimulated the search for new imaging agents labeled with '*F as well as radiopharmaceuticals featuring other radionuclides such as copper radioisotopes. Positron-emitting ®Cu (t/2 = 12.7 h) has a longer half-life than the commonly used radioisotopes for PET imaging: #F (hyp = 109.7 min) and MC (hy involving radioactivity and specialist equipment. Longer half-lives are beneficial for imaging the in vivo behavior of 0.4 min). Incorporation of !8F and "C can require elaborate synthetic manipulations targeting peptides, monoclonal antibodies, antibody fragments, and nanoparticles all of which take a relatively long time to reach their target and clear from circulation. The halflife and decay profile of Cu (B*: 1896; Ema,B* = 653 keVs 6: 39%; electron capture: 43%) offer opportunities for imaging, therapy, and theranostics at sites remote from the cyclotron production facility. In addition, °"Cu can be used as 2 companion diagnostic agent to select and plan for therapeutic applications using the B- emitting isotope ®7Cu (tyj2 = 61.9 h; B= 100%; EmeanB = 141 keV). Accurate early screening of monoclonal antibodies in preclinical studies may be assisted by the development of “Cu-labeled molecular targeting probes. The intermediate half-life of “Cu enables imaging 48 h postinjection while also limiting the radiation exposure 8.4 h), There are also positron- 32h), and Cu (tyj2= 9.7 min) that are also useful, and chemistry that has been developed using one isotope in most cases can be readily transferred to of the patient when compared, for example, to the longer lived radionuclide ®°Zr (ty ‘emitting copper radioisotopes with shorter half-lives: Cu (t/9 = 23.7 min), Cu (tyo= other isotopes. Coordination complexes have been utilized to bind metal ions to influence biodistribution or enable their incorporation into a targeting vector. The coordination chemistry of copper for radiopharmaceutical applications is dominated by theCul! oxidation state. The d? electronic configuration gives rise to a labile metal ion, of borderline hardness and coordination numbers ranging from 4 to 6 with Jahn-Teller distortions. ‘A copper radionuclide can be incorporated into a molecule or protein that has selectivity for a receptor that can target disease tissue by attaching a copper-binding ligand (chelator). It is of course important that the chelator forms extremely stable complexes with Cul and that the chelator can be “linked” to the targeting vector without compromising this stability. The chelators are required to form kinetically inert and thermodynamically stable complexes to avoid exchange of the copper to proteins in vivo. The most relevant tests of radiopharmaceutical stability are in vivo biodistribution and clearance studies. Radiolabeling must be rapid even at the relatively low “tracer” concentrations used (< 10-® mol/l) to prepare radiopharmaceuticals to take full advantage of the half-life of the radioisotope and to minimize radiation exposure to hospital staff. Radiolabeling in the presence of sensitive biomolecules is best achieved under mild conditions (37 °C or below and at near neutral pH) to maintain biological function. The chemistry used to link the chelator to the targeting vector is also an important consideration as the overall goal is to maintain the exquisite selectivity to the targeting agent. This review discusses selected recent highlights in macrocyclic bifunctional chelator design, bioconjugation techniques, and in vivo assessment toward new “Cu radiopharmacet Is with a particular focus on azamacrocycles. Extensive reviews are also available (1-5). Imaging in Biological Research, Part A Carmen S. Dence, ... Michael J. Welch, in Methods in Enzymology, 2004 Overview of the Quality Assurance of C-11 Radiopharmaceuticals Radiopharmaceuticals administered for PET procedures and which contain radionuclides of very short half-lives, such as carbon-11 (20.4 min), must be analyzed, must meet quality assurance specifications, and must be fully documented prior to administration to humans.!°2) This requires various types of quality control (QC) determinations, such as radionuclidic identity, radionuclidic purity, radiochemical and chemical purity, sterility, and pyrogen testing. Itis important that each analytical test be validated and the limits for each test specified. c Identity This can be accomplished prior to release of the radiopharmaceutical by decay analysis using a dose calibrator computer Radionuclic program to calculate Ty/p. Radionuclidic Purity The fraction of total radioactivity that is present as the specified radionuclide should be determined from a y-ray spectrum by means of a multichannel pulse height analyzer or a germanium detector to detect the presence of any Y photon energies other than 0.511 MeV and the sum peak at 1.02 MeV. The radionuclidic purity determination can be made three to four half-lives after the end of bombardment with litle interference from the main 0.511-MeV photopeak of the positron emitters. Radiochemical Purity The quality control methed for determining radiochemical purity (the fraction of the radiopharmaceutical that is present in the desired chemical form, with the label in the specified molecular position) is usually based on a chromatographic method with simultaneous mass and radioactivity detection. Various types of chromatographic methods such as thin- layer chromatography (TLC) or HPLC can be used. HPLC allows the in-line measurement of chemical and radiochemical purity. These chromatographic methods are performed using standards for the comparison of Rr values and retention times or for generating standard calibration curves.!? Radioactivity Balance For the development of new radiopharmaceuticals requiring analysis by HPLC, it is generally necessary to perform 2 radioactivity balance measurement to ensure that the total radioactivity injected onto @ HPLC column is recovered at the end of the specified HPLC run time. This determination can be made by injection of an aliquot of the radinnharmareuitical (100 ull anto the HPI C and eallecting all the nostiniectian effluent solvent in a voliumetric flask‘The flask is then taken to the standard volume and mixed well. For example, for an HPLC run at 1.5 ml/min that lasts 10 min, a 25-ml volumetric fask is used to collect the eluate. After 10 min the flask is removed from the eluting line and a sufficient volume of water (or a solvent compatible with the HPLC solvent used) is added to bring the total volume to 25, ml. This constitutes “sample counts.” The “standard counts” sample is obtained by aliquoting the original volume injected on the HPLC column (10-50 il from the same original analyte) into another 25-ml volumetric, and adding sufficient solvent to bring the total volume to 25 ml. An aliquot from each volumetric flask is transferred into a test tube, and the samples are counted in a sodium iodide y counter. Due to the short halflife of C-11, itis necessary to decay correct both samples to time zero and compute the percentage eluted as follows: (“counts in sample”/“counts in standard”) x 100. Acceptable values should be 85% or higher. With high specific activity radiopharmaceuticals, some radioactivity losses are unavoidable on the HPLC tubing, column, precolumn, filters, etc. Values below 85% are usually indicative of radioactivity being retained on the chromatographic column or precolumns that need to be addressed in order to avoid inaccurate radiochemical purity determinations. Chemical Purity Analyses are required to verify the absence of any chemical impurities or solvent residues in the final preparation. ‘Analyses also require an injection of a known standard each time a QC is performed. In this way the accuracy of the HPLC, or of any other system that is used, is determined each time. Chemical impurities separated by HPLC are generally easy to detect if they are ultraviolet (UV) absorbing. Compounds with low UV absorption characteristics can be detected by pulsed amperometric detectors (PADs) or by HPLC mass spectrometry. The chemical purity requirement serves to verify the chemical identity of the product and by-products, including stereoisomeric purity, if needed (eg, 1 [C]d- glucose versus 1-[!C]d-mannose). lon chromatographic techniques are applied routinely to the detection of residual inorganic species in order to validate the absence of nickel, borate, and lead ions. Lead ions may potentially arise from the lead counterion of the Aminex resin of the HPLC column used in the preparative purification of the 1-['4Cjd- glucose preparation. The quantification of organic solvent residues such as ethanol, acetonitrile, and ether used in the preparation of the carbon-11 compounds is performed by gas chromatography. Separation is carried out on a Varian 3800 gas chromatograph using a capillary column DB-Wax, 30-m x 0.53-mm id., 1-um film thickness (J&W Scientific. The injector and FID detector temperatures are held at 225° and 275°, respectively. Helium is used as a carrier ata flow rate of 7 ml/min. The column temperature is held at 40° for 2 min and is raised to 110° in 7 min. Analyses are performed on a 1.0-pl aliquot of the final injectable solution after sterile filtration. ty, Apyrogenicity, Isotonicity, and Aci Tests should be performed to ensure sterility, apyrogenicity, isotonicity, and suitable acidity (pH) before administration to humans. Sterility should be determined postrelease on each batch of parenteral radiopharmaceutical intended for human use. The injectable drug product must be sterilized by filtration through a 0.22-pm filter as a final step in the radiosynthetic procedure. USP methods for sterility require inoculation of the radiopharmaceutical into both tryptic soy broth and fluid thioglycolate media within 24-h postend of synthesis (EOS). Because an entire lot of a PET radiopharmaceutical may be administered to one or several subjects, depending on the radioactivity remaining in the container at the time of administration, administration of the entire quantity of the lot to a single patient should be anticipated for each lot prepared. Verification of apyrogenicity should be made using the USP bacterial endotoxin test (BET) on each batch of every nongaseous radiopharmaceutical prepared for intravenous human administration. The USP limit for endotoxins is 175 endotoxin units (EU) per volume (V), which is the maximum volume administered in the total dose. If the Typ 2 20 min, a 20-min endotoxin “limit test” must be performed prerelease (USP 46). A standard 60-min test must also be performed on each batch. The pH and isotonicity can be adjusted to physiologic values prior to the final filtration by the addition of sterile buffers or by a 0.9% sodium chloride solution Radiopharmaceuticals for Diagnosis and Therapy M. Elisa Crestoni, in Reference Module in Chemistry, Molecular Sciences and Chemical Engineering, 2018Introduction Radiopharmaceuticals are biologically active molecules labeled by radionuclides which provide a beneficial source of ionizing radiation mainly applied in diagnostic imaging and therapy. Since they are administered mainly by the intravenous route, sterility, apyrogenity and all quality control parameters must be carefully verified. (On the whole, short-lived radionuclides emitting either B* particles (positrons) or Y-rays are employed in diagnosis, whereas Auger electrons and cand (electrons) emitters are administered in therapy. In some rare cases, the same element (eg, the diagnostic radionuclide Cu and the therapeutic radionuclide Cu) or even the same radionuclide (e.g, 131))is used for both purposes. Radiodiagnostic imaging is a rapid, non-invasive procedure where very low concentrations (nano to pico-molar range) of the radiotracer is perfused into the human body without causing any pharmacological effect, and thus providing evaluation of physiology, early detection of disease and real-time monitoring of the effects of treatment. Such strategy, which eventually facilitates deployment of therapies and supports efforts to attain “personalized medicine and tailored therapy” by the control of individual response to drug delivery, has become common practice in clinical medicine. Nuclear medicine is mainly based on two powerful, well-established imaging tools: single photon emission computed tomography (SPECT) and positron emission tomography (PET).! In SPECT, emissions, releasing energy between 30 and 300 ke, from the administered radiopharmaceutical are detected by a y camera, allowing to visualize the origin of the rays that depends on how an organ is functioning. PET exploits a radiopharmaceutical labeled with a positron emitting isotope. After a short distance, the emitted B* particle undergoes annihilation with an electron so producing a couple of, 511 keV y rays that travel in opposite directions and are then detected by a ring of detectors. The registered events, generated when two coincidence detectors are triggered synchronously, are converted into a 3D image of radionuclide distribution within the body as a function of time (Fig 1). Both modalities offer a (semiquantitative description of three-dimensional structures in deep tissues and biochemical processes at a molecular level in vivo. Although PET scans provide higher sensitivity and resolution, SPECT scans have comparatively lower costs, due to the use of more easily available, longer-lived isotopes.” Moreover, the lately developed detectors in nano-SPECT imaging make the evidences gained using the two techniques very similar. SPECT imaging is the most currently applied technique, accounting for about 95% of radiodiagnostic scans in over 40 million procedures made annually worldwide. Currently, there is an increased interest in the highly synergistic combination of PET and SPECT with either computed tomography (CT) or magnetic resonance imaging techniques (MRI). In these hybrid imaging modalities, the high sensitivity and quantification ability of PET and SPECT to reveal uptake districts and provide functional information may guide and integrate high resolution anatomic imaging of soft tissue (MRI) and bones or lung (CT).? Radiotherapeutic agents are nuclides that emit Auger electrons and B- or a particles, non-penetrating cytotoxic radiation able to kill the targeted cells or for palliative purposes. In order to reduce the risk of radiation toxicity to kidneys and bone marrow, and of DNA mutations in normal cells, therapeutic radiopharmaceuticals should have great tumor uptake and protracted residence time, besides minimal y emission. The selection of a radionuclide is crucial in the design of new radiopharmaceuticals and relies on the employment in diagnosis or therapy, appropriate half-lives and decay modes, in vivo redox stability, availability, ease of production and isolation at reasonable cost In 2014, of the 47 FDA-approved radiopharmaceuticals, 16 employ nonmetallic radionuclides, including "C, "3N, "¥F, 1231, 125), 131), 133xe, and the remaining are metallic radionuclides (radiometals), whose application is becoming prevalent, due to their wider range of nuclear and physico-chemical properties, rich coordination chemistry and availability.“* The most commonly used medical isotope is °*"Te,° the “workhorse” of modern medical imaging, incorporated into 28 FDA-approved radiopharmaceuticals. ‘The recent occurrence of a global shortage of "Mo, the parent isotope of "Te, due to long blackout periods in twoaging reactor facilities that manufacture a large part of world's supply, has led to search for possible alternatives by exploring different production strategies,” and the application of other radioisotopes.® ‘The design strategy for developing an effective radiopharmaceutical either for imaging or therapy in a personalized treatment requires an interdisciplinary approach covering knowledge of synthetic and coordination chemistry, radiochemistry, labeling and bioconjugation strategies, pharmacokinetics and therapeutics. The essential demand to minimize excessive radiation exposure by the body has prompted modern radiopharmaceutical research to develop site-specific agents, so that the radionuclide can be selectively delivered to the target tissue with minimal damage to the surrounding cells. Bifunctional chelators (BFC) are suitable ligands with the dual function of tightly binding the radiometal and forming, viaa linker, a stable conjugation with a biological targeting vector, for ‘example, small proteins, peptides, (fragments of) monoclonal antibody, nanoparticles, which exhibit strong affinity to an overexpressed tumor surface biomarker (Fig. 2). Targeted drug delivery vehicles can then be internalized by cancer cells via receptor-mediated endocytosis/phagocytosis, ensuing in high concentration of drugs in tumor tissue. All steps of the long preparation are completed before the radionuclide is incorporated, thus ensuring many half-lives of radioactivity? Selected bifunctional chelating ligands are shown in Fig. 3. Reacting functionalities include amines, carboxylic acids, activated esters, (aromatic) isothiocyanate, isocyanate, mixed anhydrides, and recently azides, epoxides and alkynes by application of click chemistry. ‘The matching between the biological halflife of the targeting vector with that of the radioisotope, as well as very high thermodynamic stability and kinetic inertness in vivo that prevent transchelation or release of the radiometal are essential to develop secure and valuable radiopharmaceuticals. Theranostic agents are targeting vectors labeled first with a diagnostic radioisotope to perform initial low dose imaging to evaluate biodistribution and clearance; then the same ligands are labeled with a therapeutic radionuclide to achieve individual therapies. ‘The methods of production for most of the applied radionuclides are based on the use of a generator or a cyclotron. The former technology takes advantage of the radioactive equilibrium between the parent isotope, in turn usually obtained by ‘a nuclear reactor, and the daughter product eluted in high-quality throughout the life of the generator. Generator- produced medical radioisotopes present various advantages, since generators are small, cost-effective, and easily transportable so allowing to attain in-house radiopharmaceuticals.* A second way to produce radionuclides is irradiation of an appropriate target with protons (p) or deuterons (4) in on-site cyclotron accelerators classified on the basis of particle energies (E, or E,) with the low-energy (E, < 19 MeV and E,< 10 MeV) cyclotrons as the most commonly used in biomedical applications. The (p.n) and (p,d) transmutations are the most common nuclear reactions adopted for medical radioisotopes. High capital costs are needed in setting up and operating such devices due to the required specialized equipment and skills. Transition Metal Groups 7 and 8 R. Alberto, in Comprehensive Coordination Chemistry I, 2003 5.2.3.1.3 Kidney- and bone-imaging agents Radiopharmaceuticals are the preferred agents for the assessment of function, as opposed to structure. Renal imaging agents are classic examples in that sense, since they allow the monitoring of the imaging of glomerular filtration and tubular secretion functions of the kidneys. Currently there are two agents available; one is °?""Te-DTPA of unknown structure, and the other one is the fully characterized [?°"TcO(MAG;)} (170). The trade name of the DTPA complex is 99Te-Penetate” and it is available from several sources. The synthesis is perfomed in a vial using pmol amounts of DTPA, with SnCl; as the reductant. The chemical composition has been the subject of many investigations and much. speculation. On the macroscopic level, the principal products formed from this reaction are dimers, with Te in the oxidation states +I, +1V, or +V.$86® However, the concentration of generator-eluted "Tc is too low for dimers to form in high concentration, and it appears likely that the active species is monomeric. The overall charge would be -1 or -2,depending on whether Te!" or Te is present. Despite the uncertainity of the structure, "Tc Penetate® is in regular radiodiagnostic use for renal-function imaging Five-coordinate [""TcO(MAGs)| (170) was introduced comparatively early in the development of radiopharmaceuticals, {itis commercially available under the trade name Technescan® (Mallinckrodt Med.) The ligand is present in the Kit in the S-protected form and requires heating in a boiling water-bath for a short time, when coordination and deprotection take place. Oxidation of excess SnCl, is sometimes required and also converts by-products into the desired complex. This compound shows good in vivo renal-clearance characteristics. Since the ligand does not have any chiral centers, one single species is formed in which the three amides and the thiolato group are deprotonated, yielding @ mono-anionic species. The terminal carboxylato group does not participate in co-ordination. Related compounds comprising diamide-dithiol ligands (dads) give rise to mono-anionic species and show very good renal-clearance properties, but have the disadvantage that they contain two chiral centers and isomer problems were ‘encountered.39349069 Complexes with 2,3-dimercaptosuccinic acid (Hdmsa, (95)}: see also Section 5.2.2.3.2(i) and glucoheptonate are of minor importance for imaging the morphology of the kidneys. The composition and the structure of the dmsa complex with 9°Te used for renal imaging is not known for certain, although the X-ray crystal structure of the Re analogue has been determined. [?"Tc-dmsa] is prepared by the reaction of Hjdmsa with ["TeO,]- in water at a pH around 3, in the presence of SnClz. The complex with *&Tcis believed to be in the oxidation state +I. When P?"TeO,) is reduced under alkaline conditions with [S,04?"a Te complex is formed with Hsdmsa, which has found use as a tumor- imaging agent. Analytical data clearly indicate that the complex obtained under these conditions is {TeO(dmsa);]-223Meso-dmsa is expected to give three different isomers with syn-endo, syn-exo, and anti orientation of, the-COOH groups with respect to the TeO group. HPLC confirmed the occurrence of al three isomers in solution from the reaction with meso-dmsa, and these are shown to be in rapid equilibrium as by "1 NMR.&455 although no structure of any of the isomers of [TeO(dmsa);]" (640) is available, the structure of syn-endo-[ReO(dmsa)y}- has been described and shows the expected square-pyramidal geometry. For renal imaging, a significant amount of the injected compound accumulates in the cortical tubules within 1 h, and remains in the renal cortex for up to 24 h. Remarkably, the complex is excreted unchanged.®% [°°"TcO(glucoheptonate);) is prepared by the reaction of calcium glucoheptonate with SnCly and ["TeO,}. The structure of the complex is square pyramidal, with an apical oxo group, and has two five-membered rings derived from the carboxylate group and the deprotonated alcohol function in glucoheptonate. The other hydroxyl functions do not participate in co-ordination and are the reason for the high hydrophilicity of the complex. The complex has also been used for brain imaging when the BBB is damaged, and the compound can diffuse into the brain. The compound is very stable in water (up to 200 days with 8Te), but is nevertheless used extensively as a precursor for further substitution reactions in which the glucoheptonate ligands are replaced by more potent chelators. When used as a renal-imaging agent, the complex is excreted by glomerular filtration, and half-life in plasma is only a few minutes.67 Both complexes are not now used extensively in clinics, as other diagnostic methods such as MRI or ultrasound give clearer images of renal morphology. Complexes of "Te with phosphonate ligands are widely used as diagnostic agents for the detection and monitoring of metastatic disease in bone and bone infarction infections. The ligands are in general diphosphonates, with various types of substituent on the backbone. Major ligand types in that respect are methylene-diphosphonate (mdp, (635), hydroxymethylene-diphosphonate (hmdp, (636), 1-hydroxyethylidenediphosphonate (hedp, (637), and 1-hydroxy-4- amino-butylidene-1,1-diphosphonate (abp). The preparation of the complexes is standard for radiopharmaceutical use and is performed by reduction of ["TcO,]- with SnCl; or [BH,)"in the presence of the ligand. The reaction yields product mixtures, and the exact compositions or structures have yet to be determined. Nevertheless they are very effective bone-imaging agents. The presence of uncoordinated phosphate oxygen provides a mechanism for absorption of the complexes on the surface of newly formed hydroxy-apatite. In this respect they can be considered to act as ligands for exposed Ca on the newly formed crystals of hydroxy-apatite. Many efforts have been made to characterize the complexes formed by the reaction of various °Te starting materials with phosphonates such as (635) or (636). Size- ‘exclusion chromatography or mass spectrometry suggests the complexes are polymeric.6™* Unfortunately, but unically far nalumare the eamnacitinn nf the nenductdenande etennaly nn the raactinn ennditinne and ie cianiBeanthedifferent when pH or concentration are altered.” From spectrophotometric measurements it was concluded that the oxidation state of Te in [Te-(hedp]] is +IV; however, polarographic studies suggested mixed oxidation states, involving Te! Te”, and Te¥.7" The structure of one mdp complex has been elucidated. The reaction between [TeBre]® and excess (635) gave brown crystals, and the X-ray crystal structure showed a polymeric chain structure of stoichiometric composition {Te(OHXmdp]... Each ligand (635) bridges two symmetry-related technetiums, and each Te atom is bound to two mdp ligands. The polymeric repeat is completed by an oxygen atom, probably a hydroxo group which bridges two Te atoms. ‘The geometry is approximately octahedral, but the oxidation state cannot be unambiguously assigned since itis not clear whether a hydroxy or an oxo group bridges the two technetium atoms.” The structure shows that diphosphonates can act as bidentate ligands and can bridge metal centers, as is the case for their binding to Ca™* in bone. Raman, spectroscopy suggested that for the hedp complex both [TeO]** and [OTcO}* may be present, with bands observed at 970 em”! and 878 cm-!.73 The amount of skeletal uptake of the species obtained from the phosphonate ligands lies in the sequence [”""Te-hmdp] > [??"Te-mdp] > °9""Te-hedp]. This reflects the general observation that the biodistribution of ®"Te-based radiopharmaceuticals are significantly altered by even small changes in the ligand structure 7™Scheme (80) Application of 18F-PET Imaging for the Study of Alzheimer's Disease Kjell Nagren, Juha ©. Rinne, in Fluorine and Health, 2008 3 CONCLUSIONS 18f-Labeled radiopharmaceuticals have a special advantage for clinical and academic PET studies due to the relatively long halflife of #F. The radiotracer can be used for several sequential PET studies of different patients, and it can also be shipped to remote PET centers that do not have a production of radiopharmaceuticals. [!°F]FDG is already an established tool in the diagnosis of patients with AD. A few ™F-labeled tracers for serotonin receptors and amyloid plaques have also proven to be useful in the study of AD. There are several examples among other recently developed 'F-labeled tracers, that have potential for this imaging purpose. [!*F[Fallypride can be used to study both striatal and extrastriatal dopamine Dz receptors. [!5F]A85380 is promising for the study of Bz subtypes of the nAChRs. Several "labeled substrates for [ACHE or BUChE have been developed that are also promising for the study of new drugs for these enzymes. Tracers such as ['5FJFEDAA1106 can be used to study microglial activation. H) receptors have been shown to be dramatically reduced in AD by using a "C-labeled tracer, but we are still waiting for the development of the first useful !F-labeled tracer for Hy or other types of histaminergic receptors. The development of specific ligands for various neurotransmitter systems could eventually help in the early detection, differential diagnosis, or evaluation of different treatments for AD. Insights from Imaging in Bioinorganic Chemistry Richard Southworth, ... Philip . Blower, in Advances in Inorganic Chemistry, 2016 2.1 From Serendipity to Design The "Te-labeled radiopharmaceuticals that came into widespread daily use in the 1970s were largely a product of early biological experiments in which complexes were made with “off the shelf” chelating ligands selected in the absence of detailed knowledge of the coordination chemistry of technetium (1). In most cases their structures remain unknown even now, and their approval in today’s regulatory climate would have been most unlikely. Nevertheless, they were extremely successful and medically useful. Examples (Figure 1) include DTPA (1), meso-DMSA (2), bisphosphonates (3), HIDA (4), and various colloids (predating “nanotechnology” by decades) and macro-aggregates made from albumin, In the 1980s and 1990s, as understanding of the coordination chemistry of technetium grew (6), a new generation of complexes found their way into nuclear medicine, with a greater element of chemical design in their development and saith wall daRinad ebeuctiear het till ith eimnla Lit-harad euntharie It hanma clanr that harstiea nf tha mrantar anvialantss tenes me ove ayrnnsie ee character and greater pi-bonding tendency (both ligand-to-metal and metal-to-ligand, depending on oxidation state) shown by technetium compared to other metals discussed in this chapter, polydentate chelators were not always necessary and bidentate and even monodentate ligands would provide sufficient in vive kinetic stability for many purposes (1). The concept of technetium “cores” emerged—that is, a set of well-defined stable complex building blocks adapted to the coordination preferences of technetium (and in most cases, importantly, to rhenium too) that could be elaborated and functionalized for different purposes. Examples (Figure 2) include the TcO** with mixed tetradentate sulfur and nitrogen chelating ligands such as the MAG3 complex (5) for renal function imaging, “pentavalent” DMSA complex (6) for medullary thyroid carcinoma and bone disease (7-15), HMPAO complex for cerebral perfusion imaging and cell labeling (7), (8, eg, sestamibi for myocardial perfusion imaging), (with tetraamine 9 or diphosphine 10 chelating ligands), (11), and TeN(dithiocarbamate), (12) (16-20). Some of these are discussed in more detail below. Fluorine-18 Chemistry for Molecular Imaging with Positron Emission Tomography Frédéric Dollé, ... Marie-Claire Lasne, in Fluorine and Health, 2008 2.2 Design of radiotracers and radiopharmaceuticals labelled with a short-lived positron emitter: The case of fluorine-18 The design of radiotracers or radiopharmaceuticals labelled with short-lived positron emitters requires beside the inescapable selection of a chemical structure of interest to be labelled the choice of the radionuclide to be used. The selection of a chemical structure is generally based on already existing and available information. Within the framework of receptor studies for example, the pharmacological characterisation of the target molecule is crucial. Qualitative data, such as selectivity, specificity, antagonist or agonist character, and quantitative data, such as affinity (Kp, K,, C50) and localisation and number of binding sites (8,,.), permit to classify potential candidates. Also other biological information, such as efficiency (EDsp), toxicology (LDsq) and pharmacokinetics as well as physico-chemical information, such as the partition coefficient, can influence the final selection. When known or foreseeable, the metabolic parameters of the target molecule can come into play. Other considerations, such as availability of the radionuclide, dosimetry of the radiotracer and its possible metabolites as well as radiotoxicity of the radioisotope, may have their say. The choice of the radionuclide and the position of the labelling are generally determined by the chemical structure of the target molecule to label and the ease of introduction of the radionuclide from a chemical point of view. The physical half life of the radionuclide should however match the timescale of the studied process. For example, in repeated blood flow measurements, oxygen-15 in the form of [!5O]water is ideal, while carbon-11 and especially fiuorine-18 are preferable in the study of slower processes. Native (or isotopic) labelling with fluorine-18 is limited to chemical structures already containing a fluorine atom. It implies the replacement of a native fluorine-19 atom with a fluorine-18 atom, which leaves the labelled compound with properties identical to the unlabelled one. The small isotope effect is negligible [22]. However, there are only a very limited number of molecules in living nature that contain fluorine. In fact, those fluorine-18-labelled radiotracers and radiopharmaceuticals that are based on natural molecules are always an analogue of the parent compound by hydroxy for fluorine or hydrogen for fluorine replacement, which is called foreign labelling [7,23]. Some controversy exists as to whether fluorine can be considered as isosteric to hydrogen. Fluorine has a small van der Waals radius of 1.33 A, closer to that of oxygen (1.40 A) than to that of hydrogen (1.20 A) [24,25]. The C-F bond length, 1.38 A, is comparable with that of C0, 1.43 A (CH, 1.10 A) [24,26,27] Finally, fluorine is also the most electronegative atom according to Pauling’ scale, with the electronegativity of fluorine (4.0) close to that of oxygen (3.5) (only 2.2 for hydrogen). The carbon-fluorine bond is therefore highly polarised, generating a strong dipole moment in the molecule, favouring hydrogen-bond formation [28]. In any case, foreign labelling with a fluorine-18 atom changes the molecule's physical properties and consequently ite hinlaaical and nharmacalnaieal nranertiae [26] The lahellina ctratemy chauild he diractad tawarde thace nncitinne thatwill cause as little effect as possible on the characteristics of the parent molecule. An ever expanding field in fluorine-18 chemistry concerns drug and drug like compounds generated by the pharmaceutical industry [3,7,29]. These can be subject to native labelling if they contain a fluorine at a suitable position or to foreign labelling if they do not. Insights from Imaging in Bioinorganic Chemistry Benjamin P. Burke, ... Stephen J. Archibald, in Advances in Inorganic Chemistry, 2016 2.2 Gallium-68 ‘The most widely used ligand in radiopharmaceutical chemistry for “Ga is still DOTA (1,4,7,10-tetraazacyclododecane) and it remains the standard for “"Ga-PET design. The dominance of DOTA stems from its use in other imaging modalities and hence the widely available commercial analogues suitable for targeting vector conjugation, along with its ability to form complexes of sufficient stability (23). Similar to labeling with copper-64, DOTA requires elevated temperatures and a relatively low pH for the efficient incorporation of gallium-68 (24). This is partly caused by the requirement to incorporate the metal ion into the macrocyclic cavity rather than for it to be encapsulated by pendant arms above a face-capping macrocycle. NOTA, which has been shown to be an effective chelator for in vivo coordination of gallium-68, provides a smaller cavity tridentate macrocycle and three pendant arms to wrap around the metal center. The use of NOTA allows radiolabeling at room temperature which has led to conjugation to a wider variety of targeting vectors. A structural variation of the NOTA ligands incorporating phosphonate pendant “arms,” developed by Parker etal in 1994, has been studied in detail by Notni and coworkers as already mentioned in Section 2.1 (TRAP and NOPO) (25). ‘The attached phosphonate arms facilitate rapid complexation of gallium-68 by forming an “out-of-cage” complex initially which directs the metal toward the macrocycle, resulting in the formation of a stable complex. (24,26) These ligands show a high affinity and specificity for gallium-68 and are less influenced by impurities during labeling in comparison to other established ligands (NOTA and DOTA) (27). Although acyclic ligands had been neglected for several years as the initial chelators tested did not provide sufficient stability with gallium-68 (EDTA, DTPA), they have recently experienced a renaissance. Tris(hydroxypyridinone) derivatives based on the core CP256 derivative have been developed by Blower and coworkers and radiolabel at a lower concentration than NOTA at room temperature (Figure 6), which could lead to higher specific activity tracers (28). This property combined with the ability to perform radiochemistry at pH 7 to form complexes stable to transchelation makes this chelator type promising for development of targeted radiopharmaceuticals with a wide range of biomolecules. Another acyclic ligand type which has shown sufficient stability for in vivo work is the dedpa family developed by Onvig and coworkers (29). Most recently, the development of the rigidified backbone forming H>CHXdedpa which has been modified with nitroimidazoles for hypoxia imaging has shown the flexibility of this chelator scaffold (23,30). The major advantage of this chelator family could be their versatility, showing promising results fora range of radiometals for imaging and therapy (154,31). Parker and coworkers attempted to combine the advantages of macrocyclic and acyclic ligands in a hybrid derivative based on the 6-amino-1,4-diazepine-triacetic acid core: the DATA ligands (Figure 7) (32). These ligands provide high complex stability combined with biomolecule compatible labeling characteristics, room temperature in a pH range of 4 7. Besides the developments in ligand design, the more “practical” side of gallium-68 radiolabeling must be addressed. Due to the high zine(\!) concentration (°%Ga decay product) and high proton concentration (acidic generator eluate) hindering complex formation, gallium-68 must be formulated before reaction by “post processing.” Recent studies have focused on simplifying the procedure and by using solutions compatible with direct administration (33). (One of the biggest challenges of gallium-68 radiopharmaceuticals so far has been the development of a kit-type setup or dose-on-demand system, in order to replace the work horse of nuclear medicine: technetium-99m radiopharmaceuticals (34), Its convenient accessibility via a generator system and complex formation at room temperature within a few minutes have made it the most widely used SPECT nuclide in clinical application. As the spatial resolution of PET is stilconsidered to be higher than that of SPECT (human scanners) along with the worldwide shortage of ” Mo for ”""Te generator production, there is an obvious benefit to developing a similar setup for gallium-68 (35). The only obstacle which is still to be overcome is the development of a system which can make tracers in a “dose-on-demand” fashion that an be operated simply by a radiopharmacist. This could be achieved via a kit-like system, analogous to °""Tc tracers, which label from a lyophilized sample or from a solution (36). Using a lyophilized kit which radiolabels at ambient temperature, physiological pH, within a few minutes, not requiring subsequent purification is the goal of gallium-68 chemistry which will certainly be realized within the next few years. The transfer of the radiochemical reaction onto microfluidic or lab-on-a-chip setups is another promising field which is currently being evaluated. Tests using standard ligands show remarkable reproducibility and yields (37). However, neither ofthese methods avoid the prereaction preparation of gallium-68 and although current technologies can be modulated for automation, the complexity of the process outweighs the inherent advantages of gallium-68. A solution to this problem could be the development of a “dose-on-dernand” microfluidic system in which all processes were simplified and automated on-chip. However, particle-based commercial ion-exchange resins currently used for gallium-68 preparation are incompatible with microfluidic systems due to their relatively high back pressures. The development of technologies to open the door to microfluidic preparation and radiolabeling would be a significant development in the field toward “dose-on-demand” clinical tracer production. Lomefloxacin Reem |. Al-Wabli, in Profiles of Drug Substances, Excipients and Related Methodology, 2017 2.4.1 Radioimmunoassay Methods. Motaleb [58] developed and optimized a new radiopharmaceutical method for infection imaging. Technitium-99" was added to lomefloxacin in the presence of SnClp. The radiochemical yield of ®°"Te-lomefloxacin was of 93.6%. Induction of Staphylococcus aureus infection in the left thigh of the rats was used to study the biodistribution of the drug, The ratio of bacterial infected thigh/contralateral thigh was evaluated both thighs of the rats. °°”"Te-lomefloxacin showed higher uptake (T/NT = 6.5 + 0.5) in the infectious lesion °9"'Te-ciprofloxacin (T/NT = 3.8 + 0.8). Tewson et al. [59] labeled lomefloxacin with fluorine-18 to study the biodistribution of the drugin the human body. A preliminary human study using positron emission tomography was carried out. The exchange reaction between fluorine- 18 fluoride and the fluorine-19 on the lomefloxacin was 40% after 1 h in DMSO. The drug is distributed in the whole- body tissues except the brain, View full topic index